Because retroviruses like HIV-1 evolve so rapidly, viral genetic sequences retrieved from just a few decades before present are effectively molecular 'fossils'. Such fossil sequences can be used to provide indisputable evidence of the existence of a given microbe at an early time point, to validate historical inferences that could otherwise not be tested, and to provide insight into the current evolution and dynamics of the AIDS pandemic. They light up portions of the deep past that would otherwise be lost, and can provide the means to test important hypotheses about the origins, pathogenesis, adaptation, spread, persistence, and transmission dynamics of medically important viruses. The battle to control HIV requires the best possible understanding of its current genetic diversity, and such understanding can best be achieved by viewing contemporary gene sequences in the context of historical genetic variation. With just a handful of exceptions, the 'molecular archeology'perspective has to date not been exploited with respect to HIV-1 group M, the focus of this proposal. The overarching aim of this project is to make a comprehensive and integrated effort to understand the future of HIV-1 group M by recovering then analyzing information gleaned from its past. To accomplish this we will aim 1. to use archival specimens from the 1970s to uncover the history of the origin and emergence of HIV-1 in North America;2. to recover and analyze near- full-length envelope gene and, if possible, genomic HIV-1 sequence from multiple paraffin- embedded tissue samples from the 1960 and perhaps earlier;3. to investigate the early genetic diversity of HIV-1 group M in central Africa and how it informs understanding of the current genetic diversity in this important region by screening large numbers of archival samples for HIV-1 and conducting sequence and phylogenetic analyses on the resulting data set. Crucially, we have assembled a massive collection of archival specimens, many from sources that have not yet been widely considered in the field of HIV research, with which we will illuminate the remarkably unstudied early phase of HIV evolution (from around the time of the discovery of AIDS, back to 1960s and perhaps even earlier) right up to the present day. Our expertise and track record make us uniquely positioned to conduct this important research. PUBLIC HEALTH RELEVANCE: This work is relevant to public health since it is concerned with the natural history of HIV/AIDS: how the AIDS pandemic originated, spread, and evolved up to and including the present day. It will provide understanding of the past and present genetic diversity and dynamics of HIV-1 group M and may thus be of use in controlling the current pandemic and preventing future jumps of AIDS viruses into humans.